The tetO-208 TDP-43 transgene has the Tet-responsive element (TRE or tetO) and mouse prion protein promoter sequences (PrP or Prnp) directing expression of amino acids 208-414 from human TDP-43 (TARDBP). Accumulation of the TDP-43 C-terminal fragment (208 TDP-43 CTF) is associated with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) in human brain.
When these tetO-208 TDP-43 transgenic line 2 mice are exposed to tetracycline-controlled transactivator protein (tTA) or reverse tetracycline-controlled transactivator protein (rtTA), 208 TDP-43 CTF expression in the resulting animals can be regulated with tetracycline or its analog doxycycline (dox).

Breeding the B6C3F1 tetO-208 TDP-43 mice to C57BL/6J-congenic mice with forebrain-specific tTA expression (from Stock No. 003010) results in bigenic Camk2a-tTA/tetO-208 TDP-43 animals (CAMK-208 TDP-43 Tg). Following dox withdrawal, those CAMK-208 TDP-43 Tg mice exhibit highly-insoluble TDP-43 CTF accumulation in neuronal cytoplasm and dendrites, without formation of the large cytoplasmic TDP-43 inclusions seen in FTLD-TDP and ALS tissue. Hippocampus showed progressive neurodegeneration and astrogliosis in the dentate gyrus (DG), accompanied by phosphorylated TDP-43 in the CA1 subfield and ubiquitin and mitochondria accumulations in the stratum lacunosum moleculare (SLM) layer. The observed neurodegeneration was without changes in the level, solubility or subcellular distribution of nuclear endogenous full-length TDP-43, and was also independent of TDP-43 phosphorylation. After 13 months of transgene expression (off-dox), resumption of dox-treatment led to rapid clearance of 208 TDP-43 CTF and phosphorylated TDP-43, which ameliorated neuron loss in the DG despite persistence of ubiquitin accumulation in the SLM.

In addition, breeding B6C3F1 tetO-208 TDP-43 to NEFH-tTA line 8 mice (broad tTA expression in brain but only modest levels in DG granular cells; see Stock No. 025397) results in bigenic NEFH-tTA/tetO-208 TDP-43 animals (NEFH-208 TDP-43 Tg). Following dox withdrawal, NEFH-208 TDP-43 Tg exhibit similarities to CAMK-208 TDP-43 Tg - including high levels of insoluble 208 TDP-43 CTF in the cortex and hippocampus, with accumulation of p409/410 TDP-43 predominantly in the CA1 region and ubiquitin in the SLM region of the hippocampus. Uniquely, NEFH-208 TDP-43 Tg show no overt loss of DG neurons up to 19 months (as <5% of DG cells expressed 208 TDP-43 CTF).

The donating investigator reports that hemizygous tetO-208 TDP-43 transgenic mice are viable and fertile with no observed phenotype defects or behavioral abnormalities, and they have not tried to generate homozygous mice to date (September 2016). The transgene insertion site(s) is not known. Multiple copies are likely, however, as the inducible expression level of TDP-43_208-414 in hemizygous mice is 3-6-fold greater than endogenous TDP-43 levels.

Note on tetO/Prp promoter: While the untranslated sequences from Prnp have been shown in other mouse models to result in minimal levels of transgene expression in the brain before Tet-induction (see Stock Nos. 025104/027783), it has not yet been determined if these tetO-208 TDP-43 transgenic line 2 mice exhibit any such expression before Tet-induction (September 2016).